In order to achieve a desired effect of propolis phenolic compounds in the skin, it is important to develop semisolid systems with propolis products that would efficiently release and deliver these compounds into the skin. The aim of the study is to justify the modeling principles of semisolid formulations with propolis products, to optimize experimental semisolid formulations, and to formulate a quality model based on biopharmaceutical studies. The penetration of individual phenolic acids (vanillic, caffeic, p-coumaric, and ferulic) and vanillin from aqueous propolis extract and experimental propolis semisolid formulations (ointment, water-in-oil cream, hydrogel, and oil-in-water gelified cream) into the human skin ex vivo have been evaluated. An active role of the semisolid system in releasing and influencing the penetration of propolis active compounds into the skin has been confirmed. The distribution of investigated phenolic compounds in the layers of skin (epidermis and dermis) was evaluated and linked to different lipophilicity. Relatively lipophilic compounds (ferulic and p-coumaric acids) accumulated in the epidermis and relatively hydrophilic compounds (vanillic acid and vanillin) migrated to the dermis. Caffeic acid, which was present in analyzed propolis products at lower quantities as compared with other phenolic acids, was determined only in the epidermis. The design of experiments was applied for the optimization of the composition of dosage forms. Optimization parameters allowed predicting the release of propolis active compounds from investigated semisolid formulations.